Special Issue "Re-Irradiation, Chemotherapy, New Drugs for the (Re)-Treatment of Recurrent Gliomas"

Guest Editor
Dr. Brigitta G. Baumert
Department of Radiation-Oncology (MAASTRO), Maastricht University Medical Centre (MUMC) and GROW Research Institute, The Netherlands
Website: http://www.maastro.nl/
E-Mail: brigitta.baumert@maastro.nl
Interests: CNS tumors; sarcomas; pet imaging; new MRI imaging techniques introduced for radiation therapy; new international trials in primaruy and secondary brain tumors

Dear Colleagues,

Gliomas account for ca. 70% of all primary brain tumors. Malignant glioma include all glioma with a WHO grade III and IV where the glioblastoma multiforme (WHO IV) is the most malignant and common tumour (ca. 60%). For glioblastoma, combined postoperative chemoradiotherapy with temozolomide is the current standard medical practice after results of the joint EORTC-NCIC phase III study randomizing between radiotherapy alone and combined chemoradiotherapy with temozolomide showed a significant improvement in 2-years survival from 8% to 24% for the combined treatment arm and is associated with 5 year survival estimates in the region of 10% [1,2]. It was shown, that survival favoured combined primary treatment despite salvage treatments given. However, a large proportion of patients relapse within 18 months after first treatment. Also many patients harbouring an anaplastic glioma experience either a transformation of the glioma into a higher grade or a local recurrence after primary treatment. Currently, there is no standard salvage treatment at recurrence defined. Re-treatments considered are  re-resection, second line chemotherapy or novel agents or re-irradiation.

Challenges for second line chemotherapy are fact that many patients have reduced bone marrow capacity after first line chemotherapy as well as the fact that in a subgroup of patients who responded well to temozolomide at first line treatment, developed resistance mechanisms to temozolomide at relapse. (Re)-resection cannot be curable due to the highly invasive nature of glioma cells into surrounding normal tissue. Re-irradiation carries concerns of late toxicity. New drugs with anti-angiogenic characteristsics for example of other targeted drugs open new doors for potential treatment combinations.

Future treatment approaches point into the direction of combined multi-disciplinary treatment approaches like in the primary situation. Recurrent glioma also open the possibility to testing new treatments and new treatment techniques within prospective controlled trials also as these patients are best treated within clinical trials.

These edition shall collect and present the current available knowledge on re-treatment options as well as potential future developments and current research.

For this issue and in regard to the malignant glioma, possible topics of interest may include:

Retreatment approaches either with a single treatment option like second line chemotherapy, re-operation, re-irradiation or new targeted drugs or new combined multi-disciplinary approaches combining for example, targeted drugs with irradiation or vaccination with operation, application of new imaging techniques like PET imaging or new functional MRI imaging (perfusion, diffusion) etc.

Regarding new treatment techniques, stereotactic radiotherapy, brachytherapy, proton therapy, carbion therapy, new neurosurgical techniques or current reserach on new targeted drugs, vaccination or immunotherapy for example, are of interest.

Regarding cancer biology, possible topics of interest may include cancer stem cells, resistance to MGMT, new potential targets in malignant glioma.

Regarding clinical outcome survival, local control either clincally or radiologically, toxicity, morbidity, and efficay are topics of interest.

Dr. Brigitta Baumert PhD
Guest Editor

References:

1. Stupp, R.; Mason, W.P.; van den Bent, M.J.; Weller, M.; Fisher, B.; Taphoorn, M.J.; Belanger, K.; Brandes, A.A.; Marosi, C.; Bogdahn, U.; Curschmann, J.; Janzer, R.C.; Ludwin, S.K.; Gorlia, T.; Allgeier, A.; Lacombe, D.; Cairncross, J.G.; Eisenhauer, E.; Mirimanoff, R.O.; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl. J. Med. 2005, 352, 987-996.

2. Stupp, R.; Hegi, M.E.; Mason, W.P.; van den Bent, M.J.; Taphoorn, M.J.B.; Janzer, R.C.; Ludwin, S.K.; Allgeier, A.; Fisher, B.; Belanger, K.; Hau, P.; et al. on behalf of the European Organisation for Research and Treatment of Cancer Brain Tumour and Radiation Oncology Groupsthe National Cancer Institute of Canada Clinical Trials Group. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009, 10, 459-466.

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• malignant glioma
• recurrence
• re-irradiation
• re-treatment
• re-operation
• targeted drugs

Type of Paper: Article
Title: A Novel Therapeutic Strategy for the Treatment of Glioma, Combining Chemical and Molecular Targeting of Hsp90α
Authors: Adi Mehta, Leroy Shervington, Chinmay Munje, Amal Shervington
Affiliation: Brain Tumour North West, Faculty of Science and Technology, University of Central Lancashire, Preston, PR1 2HE, UK; E-Mail: aashervington@googlemail.com
Abstract: Hsp90α’s vital role in tumour survival and progression together with its highly inducible expression profile in gliomas and its absence in normal tissue and cell lines validate it as a therapeutic target for glioma. Hsp90α was downregulated using the posttranscriptional RNAi strategy (sihsp90α) and a posttranslational inhibitor namely; the benzoquinone antibiotic, 17-AAG. Glioblastoma U87-MG cells were treated with sihsp90α, 17-AAG and concurrent sihsp90α/17-AAG (combine treatment). Both Hsp90α gene silencing and the protein inhibitor approaches resulted in a dramatic reduction in cell viability. Results showed that sihsp90α, 17-AAG and a combination of sihsp90α/17-AAG reduced cell viability by 70, 75 and 88 % (**p < 0.001), respectively,  after 72 h. hsp90α mRNA copy numbers were downregulated by 65, 90 and 99 % after 72 h treatment with sihsp90α, 17-AAG and sihsp90α/17-AAG, respectively. The relationship between Hsp90α protein expression and its client Akt kinase activity levels were monitored following treatment with sihsp90α, 17-AAG and sihsp90α/17-AAG. Akt kinase activity was downregulated as a direct consequence of Hsp90α inhibition. Both Hsp90α and Akt kinase levels were significantly downregulated after 72 h. Although, 17-AAG when used as a single agent reduces the Hsp90α protein and the Akt kinase levels; the efficacy demonstrated by combinatorial treatment was found to be far more effective. Combination therapy reduced the Hsp90α protein and Akt kinase levels levels to 4.3 % and 43 %, respectively, after 72 h. Taking into account the role of Hsp90α in tumour progression and the involvement of Akt kinase in cell signalling and the anti-apoptotic pathways in tumours, this double targets treatment infers a novel therapeutic strategy.

Type of Paper: Review
Title: Re-Irradiation Tolerance of the Human Brain and the Role of Particle Irradiation in the Treatment of Recurrent Gliomas
Authors: Peter Sminia ^1,* and Ramona Mayer ²
Affiliations: ¹ Department of Radiation Oncology, section Radiobiology, VU University Medical Center, Amsterdam, The Netherlands; E-Mail: P.Sminia@vumc.nl (P.S.)
² EBG MedAustron Ltd., Wiener Neustadt, Austria
Abstract: Malignant gliomas relapse in up to 90% in close proximity of the resection site, which is the postoperatively irradiated volume. In case that retreatment by radiotherapy is considered, the tolerance dose of the healthy brain tissue is the limiting factor for the reirradiation dose that can be applied with an acceptable morbidity profile. An overview will be presented of current available clinical data on reirradiation of glioma with respect to the tolerance dose of normal brain tissue in terms of Equivalent total dose in 2 Gy fractions (EQD2). It will be demonstrated that the tolerance dose (EQD2_cumulative) of normal brain tissue radiation approximates 100 Gy. The actually applied re-irradiation dose and EQD2_cumulative were found to increase with a change in irradiation technique from conventional- to conformal techniques like fractionated stereotactic radiotherapy to radiosurgery re-treatment, without increasing the probability of normal brain necrosis. The increase in irradiation dose significantly correlated with a decrease in treatment volume. This finding supports further dose escalation studies by the use of particle irradiation. Because of optimized physical dose distributions that can be obtained with the use of protons or carbon ions, locally, high irradiation doses can be applied to the tumour volume while sparing of surrounding normal brain tissue. Taken together, current literature shows that re-irradiation is a feasible option as palliative therapy for recurrent gliomas. Re-irradiation using particle beams will allow further dose escalation to the tumour volume with minimal exposure of normal brain tissue. It is expected that, with the introduction of particle irradiation in clinical practice, the outcome of re-treatment of glioma patients will improve, i.e., a further prolonged survival in acceptable quality of life condition.
Keywords: equivalent total dose; reirradiation; brain; glioma; late side effects, particle irradiation

Type of Paper: Review
Title: Radiation Therapy for the Treatment of Recurrent Glioblastoma Multiforme
Authors: Dante Amelio and Maurizio Amichetti
Affiliation: ATreP-Provincial Agency for Proton Therapy, Trento, Italy; E-Mail: amelio@atrep.it
Abstract: Despite the therapeutic advances in neuro-oncology most patients with glioblastoma multiforme (GBM) ultimately experience local progression/relapse. Several salvage strategies have been proposed and evaluated into clinical practice for recurrent GBM. Re-irradiation has been poorly considered in the past, mainly due to the overestimated risk of side effects using conventional radiotherapy. To date, thank to the improvement of several delivery techniques together with improved imaging capabilities, re-irradiation is an effective treatment option to manage such clinical scenario. This paper aims to provide a literature overview on the feasibility and efficacy of the different irradiation modalities for recurrent GBM. Depending on the features of the lesions, they can be managed by three-dimensional conformal irradiation, fractionated stereotactic radiotherapy, radiosurgery, intensity-modulated radiotherapy, brachytherapy and radio-immunotherapy. Re-irradiation can be employed both before and after second-line chemotherapy. Most series did not administered concomitant chemotherapy. However, some studies have been recently exploring such a strategy. In general, the clinical outcomes are consistent regardless the used technique with median survival that ranges between 8 and 11 months in most series. All modalities proved to be safe and well-tolerated. However, radiosurgery and brachytherapy are featured by higher re-operation as well as radionecrosis rates than remaining techniques. In summary, high-precision re-irradiation safely improves local control and prolongs the survival of relapsed GBMs. However, it is not a curative treatment and can be exploited only in well-selected subgroups of patients so far. Concomitant radiochemotherapy regimens deserve further investigation.

Type of Paper: Review
Title: Fotemustine, a Third Nitrosourea, could Play a Role in the Treatment of Recurrent Malignant Gliomas
Author: Patrick Beauchesne
Affiliation: Neuro-Oncologie, CHU de Nancy, Nancy, France; E-Mail: beauchesneP@wanadoo.fr
Abstract: Malignant gliomas account for approximatively 60% of all primary brain tumours in adults. The prognosis for malignant glioma patients has not significantly changed in recent years. Despite debulking surgery, radiotherapy and cytotoxic chemotherapy, median survival duration is 9–12 months and virtually no patients are cured of their illness. Fotemustine is an alkylating agent characterised by the grafting of a phosphonoalanine group onto the nitrosourea radical with consequent high lipophilia and improved diffusion through the cell membrane and the blood-brain barrier. Fotemustine has been registered for use in two indications: disseminated malignant melanoma including cerebral metastases, and primary brain tumours. Fotemustine is clinically administered as a salvage therapy for recurrent malignant gliomas and is currently used in Europe, especially in France and Italy. Myelosuppression, leucopenia and thrombocytopenia are the most frequent side effects of treatment by fotemustine. The rate of objective response is comprised between 26 to 70 %, and the median survival of 10 months was reported. New combination of drugs as well fotemustine and inhibitor of angiogenesis as bevacizumab are currently developed. In this review, we now go on to describe all the combinations of fotemustine currently in clinical use for recurrent malignant gliomas.